Therapeutic composition and method of treating patients therewith

ABSTRACT

THE NEUROLOGICAL TREATMENT OF PATIENTS USING MG ALPHAAMINO GLUTARATE HBR.

United States Patent Int. Cl. A61k 27/00 US. Cl. 424-319 12 Claims ABSTRACT OF THE DISCLOSURE The neurological treatment of patients using Mg alphaamino glutarate HBr.

The present application is a continuation-in-part of our copending applications Ser. No. 433,470, filed Feb. 17, 1965 and entitled Therapeutic Composition, and Ser. No. 318,110, filed Oct. 22, 1963 and entitled Method of Treating Patients both of which applications are now abandoned. Application Ser. No. 433, 470 is a continuation-impart of our application Ser. No. 78,778, filed Dec. 27, 1960 and entitled Composition of Matter and Method of Making the Same, and application Ser. No. 318,110 is a division of the above-mentioned application Ser. No. 78,778, now US. Pat. 3,714,486.

The present invention relates to a new composition of matter of having therapeutic properties. More particularly, the present invention is concerned with the hydrobromide of magnesium alpha-amino-glutarate, therapeutic compositions based thereon, and with a method of treating patients, particularly patients requiring neurological treatment such as sedation or muscular relaxation, for instance, but not limited to, patients sufiering from epilepsy.

While it is possible to demonstrate in vitro the stimulating effect of alpha-aminoglutarate on the metabolism of neurons, only very limited results could be obtained in attempts to treat human beings with alpha-amino'glutarate due to the difficulties in penetration of the hemato-encephalic barrier with the alpha-amino-glutarate.

It is therefore a primary object of the present invention to provide an alpha-amino-glutarate-containing therapeutic agent capable of penetrating the hematoencephalic barrier.

It is a further object of the present invention to provide treatment with alpha-amino-glutarate containing therapeutic agent capable of penetrating the hemato-encephalic barrier.

It is yet another object of the present invention to provide a therapeutic treatment which, upon proper administration, will combine the effects generally associated with the administration of alpha-amino-glutarate with a sedative effect.

With the above and other objects in view, the present invention includes a therapeutic composition which may be administered to a patient and which has a sedative effect substantially without causing toxic or depressive side effects, the composition comprising a pharmaceutical carrier and an effective amount of magnesium alphaamino-glutarate hydrobromide.

The present invention also includes as a new composition of matter, magnesium alpha-amino-glutarate hydrobromoide.

Furthermore, the present invention is concerned with a method of treating a patient having a neurological dis- "ice order which comprises the step of administering magnesium alpha-amino-glutarate hydrobromide to the patient.

Surprisingly, according to the present invention, it has been found that the hydrobromide of magnesium alphaamino-glutarate penetrates the hemato-encephalic barrier. This fact as well as the therapeutic effect of the magnesium-containing compound was confirmed by experiments with animals and by clinical tests.

On the other hand, apparently due to its bromine content, the stimulating action of the alpha-amino-glutarate is completely altered, resulting in a sedative effect on the central and neurovegetative nervous system, completely differing from that of other sedatives or tranquilizers, and, at the same time, the magnesium alpha-amino-glutarate hydrobromide does not cause any toxic or depressive eifects. In fact, it exerts a stimulating effect in cases of mental withdrawal and it is anticonvulsive in epilepsy.

Magnesium alpha-amino-glutarate hydrobromide on account of its sedative action and its efiicacy as a muscle relaxant is an appropriate medication for certain psychosomatic manifestations caused by nervous hyperexcitability, anxiety, worry, etc. and for convulsive and preconvulsive states.

Magnesium alpha-amino-glutarate hydrobromide has the empirical formula: C H O NBrMg and a molecular weight of 250.

The product has a stable structure of the chelate type as shown below:

Magnesium alpha-amino-glutarate hydrobromide is a solid, crystalline, white or slightly yellowish substance. It is easily soluble in water. It is insoluble in alcohol or ether in cold state. It is soluble in alcohol or other at elevated temperatures.

When magnesium alpha-amino-glutarate hydrobromide is heated while exposed to air, it decomposes, emitting red vapors and becomes liquid at approximately 200 C., leaving a residue which can be carbonized although only with considerable difficulty.

It is very hydroscopic; therefore, it has to be kept away from humidity. It is stable to light.

Its aqueous solutions have a pH of approximately 8 and possess a specific rotary power of -55. In a 2N hydrochloric solution, the specific rotary poyer is +32 (corresponding to alpha amino-glutaric acid).

From an acidic, nitric acid-containing aqueous solution of magnesium alpha-amino-glutarate hydrobromide, large quantities of silver bromide which is white-yellow and is soluble in ammonia may be precipitated by adding silver nitrate.

The addition of sulfuric acid and manganese dioxide to an aqueous solution of magnesium alpha-amino-glutarate hydrobromide will cause emission of red vapors of bromide, which color fluorescent paper. Bromine is likewise emitted by addition of chlorinated water, and the thus emitted bromine is dissolved, by stirring in chloroform, which then takes on a cloudy brown-reddish coloration.

The aqueous solution with a reagent for magnesium gives positive proof of magnesium.

The aqueous solution acidulated with concentrated hydrochloric acid precipitates a crystalline powder having a melting point of 195 to mation of droplets which are characteristic for alphaamino-glutaric acid.

For analytical purposes, magnesium alpha-amino-glutarate hydrobromide should be preliminarily dried in a drying chamber for two hours at 80 C.

The bromine content can be determined with a standard solution of silver nitrate and will be found to be about 30 to 31%.

The magnesium content can be determined by complexometric methods with EDTA with a pH of and ERIO T as indicator, and will be found to be equal to about 10 to 11%.

Alpha-amino-glutaric acid can be determined by polarimetry.

Nitrogen can be determined by the Micro-Kjeldhal method and, relating the result to alpha-amino-glutaric acid, it should amount to between 58 and 60%.

Essentially, according to the present invention, alphaamino-glutarate is reacted with hydrobromic acid so as to form the hydrobromide of alpha-amino-glutarate, and is further reacted with a magnesium salt so as to form the. hydrobromide of magnesium alpha-amino-glutarate as shown in Equations I and II below.

However, it is also possible to reverse the sequence of steps and to form first the magnesium alpha-amino-glutarate and thereafter treat the same with hydrobromic acid to arrive at magnesium alpha-amino-glutarate hydrobromide as shown in Equations III and IV below.

200 C. (Kofiler) under forv In order to obtain large scale production and high purity of the final product, certain precautions should be observed.

Referring first to the process of Equations I and II, one starts with alpha-amino-glutaric acid and hydrobromic acid both of which are commercially available in a state of high purity.

The two acids react with each other in stoichiometric proportions and the reaction product, i.e., hydrobromide of alpha-amino-glutaric acid can be crystallized by allowing the reaction mixture to stand for several hours at a temperature of l0 C. It is rather important to maintain an accurately controlled temperature of 10 C. during the crystallization in order to obtain a high yield.

The thus-formed crystals are washed several times with alcohol or acetone in order to eliminate any hydrobromic acid which still may be left and the presence of which is indicated by a slightly yellow coloration. Both alcohol and acetone can be easily recovered. The use of acetone is preferred, because the crystals are somewhat soluble in alcohol.

Subsequently, the crystals are dissolved in water and the thus obtained solution is neutralized with a magnesium salt until the pH of the solution is exactly 6. It is important to maintain a pH of 6 since even a small deviation from this pH value will substantially reduce the yield and the purity of the product.

The solution is then passed through a suction filter and the filtrate is concentrated until a pasty layer or film is formed on its surface; precisely at this moment, the solution is brought to a crystallizer and is kept at a temperature below 0 C. for 6 or 7 hours, i.e. the time usually required for crystallization of the magnesium alphaamino-glutarate hydrobromide.

According to the process shown in Equations III and IV, the solution of alpha-amino-glutaric acid is neutralized with a magnesium salt until a pH of between 6 and 6.5 is reached. The solution is filtered and hydrobromic acid is slowly added to the filtrate. The hydrobromic acid is added under agitation in a stoichiometric quantity relative to the alpha-amino-glutaric acid. Care must be taken to remove any excess of hydrobromic acid, because it would displace the magnesium from alpha-amino-glutarate and in such case, together with the desired product, also magnesium bromide would be obtained. Thereafter, the solution is concentrated and magnesium alpha-aminoglutarate hydrobromide recovered as described in connection with Equations I and II.

The following examples are given as illustrative only of the present invention, the invention, however, not being limited to the specific details of the examples.

EXAMPLE I grams of alpha-amino-glutaric acid are placed into an Erlenmeyer glass flask having a capacity of 500 cc. Into the flask are then poured 60 cc. of hot H O. A paste is formed thereby. Thereafter, 25 g. of hydrobromic acid are added, the mixture is agitated until almost complete dissolution of the alpha-amino-glutaric acid and then another 75 g. of hydrobromic acid are slowly poured into the flask under continuous stirring. The mixture is left at rest for an hour. Thereafter, the hydrobromide of the alpha-amino-glutaric acid is crystallized at 10 C. The crystals thus formed, provided they are pure, should be completely white. They are separated from the solution by suction filtration, cleaned and washed with 100 cc. of acetone in two portions.

g. of the thus obtained hydrobromide of alphaarnino-glutaric acid are weighed out and dissolved in 500 cc. of water and neutralized with magnesium carbonate until a pH-of exactly 6 is reached. The solution is then filtered. The filtrate is evaporated and then concentrated, for instance over a Bunsen burner, until a pasty layer of film is formed on its surface; therefore, the solution is 150 g. of alpha-amino-glutaric acid are placed into an Erlenmeyer glass flask having a capacity of 1000 cc. and are dissolved in 100 g. of boiling water. A paste is thus formed. It is neutralized by adding magnesium carbonate until the pH reaches a value of between 6 and 6.5. This operation requires vigorous stirring. The mixture is left standing for several minutes and is then filtered. Thereafter, 100 g. of hydrobromic acid are poured drop by drop onto the filtrate while the same is stirred continuously. If the solution does not stay colorless, but takes on a yellowish coloration, such coloration is removed with activated charcoal at low temperature. Then, the solution is concentrated and magnesium alpha-amino-glutarate hydrobromide crystallizes as described in Example I.

'It is very important to precisely follow the conditions as indicated in both syntheses, especially with regard to temperature control, stirring and the pH value. Not only does the purity of product depend on strict observance of these conditions, but the crystallization of the product is facilitated thereby.

Magnesium alpha-amino-glutarate hydrobromide may be administered perorally in syrup form or in the form of coated tablets, as well as in the form of capsules; or by intramuscular injection.

Daily dosages range generally from 300 to 2700 mg. per day and may be repeated for time periods ranging from a few days to several years. Irrespective of the length of time for which magnesium alpha-amino-glutarate hydrobromide is administered, no intolerance manifestations were observed as well as no signs of bromism or habituation.

A sterile solution for intramuscular administration and containing as the sole active principle magnesium alphaamino-glutarate hydrobromide may contain, for instance:

Per 1 ampoule (g.) Magnesium alpha-amino-glutarate hydrobromide 0.50 2-dimethyalmino-2,6-aceto-xylidide hydrocholride 0.02 Bi-distilled water, q.s. 5.00

In capsule form, the mixture per capsule may consist, for instance of:

Per 1 capsule (mg) Magnesium alpha-amino glutarate hydrobromide anhydrous Lactose, q.s. 330

Coated tablets containing as the only active principle magnesium alpha-amino-glutarate hydrobromide, may be produced, for instance, of:

Per Tablet g.)

Magnesium alpha-amino-glutarate hydrobromide 0.150

Magnesium carbonate talcum :1 0.120 Blueish simple syrup 0.120

Total 0.545

A syrup composition which preferably will contain as active ingredient 10-(2-dimethylamino-Z-methylethyl) phenothiazine in addition to magnesium alpha-amino- 'glutarate hydrobromide, may have the following composition:

V Per 100.00 cc. Magnesium alpha-amino-glutarate hydrobromide g 2.50 10-(2 dimethylamino 2 methylethy1)phenothiazine g 0.15 Distilled water cc 19.70 Citric acid g 0.15 Saccharin g; 0.02 Alcohol 96 c 7.50 Methyl p-hydroxybenzoate g 0.15 Essences cc 0.10 Coloring solution "cc-.. 0.05 Syrup simple, q.s. cc.. 100.00

Generally recommended dosages for intramuscular administration are between 1 and 2 ampoules daily, for peroral administration of syrup between 1 and 4 teaspoonsful daily which dosage, however, may be increased. The syrup is particularly useful in pediatrics.

Tablets and capsules generally are administered in quantities of 1-2 tablets or capsules 2-3 times daily for adults, or about half that dosage for children.

Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can be applying current knowledge readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention and, therefore, such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claims.

What is claimed as new and desired to be secured by Letters Patent is:

1. A therapeutic composition for peroral administration having sedative, muscle relaxant and tranquilizing effects and usable against neurological disorderes, said composition comprising a pharmaceutical carrier for peroral administration, and an effective amount of magnesium alpha-aminoglutarate hydrobromide.

2. A therapeutic composition for intramuscular administration having sedative, muscle relaxant and tranquilizing effects and usable against neurological disorderes, said composition comprising a pharmaceutical carrier for peroral administration, and an effective amount of magnesium alpha-amino-glutarate hydrobromide.

3. A therapeutic composition for peroral administration having sedative, muscle relaxant and tranquilizing effects and usable against neurological disorderes, said composition comprising a liquid pharmaceutical carrier for peroral administration, and an effective amount of magnesium alpha-amino-glutarate hydrobromide.

4. A therapeutic composition in unit dosage form for peroral administration having sedative, muscle relaxant and tranquilizing effects and usable against neurological disorderes, said composition comprising a solid pharmaceutical carrier for peroral administration, and an effective amount of magnesium alpha-amino-glutarate hydrobromide.

5. A therapeutic composition for peroral administration having sedative, muscle relaxant .and tranquilizing effects and usable against neurological disorderes, said composition comprising a liquid pharmaceutical carrier for peroral administration, and as effective amount of magnesium alpha-amino-glutarate hydrobromide and 10 (2- dimethylamino-Z-methylethyl) phenyltriazene.

6. A therapeutic composition having sedative, muscle relaxant and tranquilizing eifects and usable against neurological disorderes, said composition comprising a pharmaceutical carrier and an effective amount of magnesium alpha-amino-glutarate hydrobromide.

7. A method of treating a patient requiring sedationtranquillizing treatment, which comprises the step of administering magnesium glutamate hydrobromide to said patient in adaily dosage of between 300 and 2.700.,mg., the said glutamate being the compound defined in claim 1.

8. A method of treating a patient requiring anticonvulsion treatment, which comprises the step of administering magnesium glutamate hydrobromide to said patient in a daily dosage of between 300 and 2700 mg, the said glutamate being the compound defined in claim 1.

9. The method of claim 7, wherein the said glutamate is administered perorally.

10. The method of claim 8, wherein the said glutamate is administered perorally.

11. The method of claim 7, wherein the said glutamate is administered by intramuscular injection.

12. The method of claim 8, wherein the said glutamate is administered by intramuscular injection.

References Cited UNITED STATES PATENTS 1,440,269; 12/1922 Berendes. 2,132,351 '10/193'8 Dorzbach. 3,051,618 8/1962 Ehrhart.

OTHER REFERENCES Merck Index, 7th edition, Merck and Co., Inc., Rahway, N.J., 1960, pp. 608 and 857.

Ellis et al.: Progress in Medical Chemistry, I, Butterworths, London, 1961', pp. 9294.

STANLEY I. FRIEDMAN, Primary Examiner U.S. Cl. X.R. 

